Derivatives of 2,3-norbornanedicarboxamide

ABSTRACT

1. A COMPOUND HAVING THE FORMULA   2,3-(-CO-N(-(CH2)N-N(-R4)-R5)-CO-),5-(HO-)-NORBORANE   IN WHICH N IS AN INTEGER OF 2 TO 4 INCLUSIVE AND EACH OF R4 AND R5 ARE H OR (LOWER)ALKYL OR WHEN TAKEN TOGETHER WITH THE NITROGEN A RADICAL OF THE FORMULA   MORPHOLINO-, 4-R6-PIPERAZINO-, PYRROLO-, PIPERIDINO-   IN WHICH R6 IS (LOWER)ALKYL; OR AN ACID ADDITION SALT THEREOF.

United States Patent 3,850,921 DERIVATIVES 0F 2,3-NORBORNANEDI.CARBOXAMIDE Ichiro Matuo, Tokyo, Japan, and Sadao Ohki, 624705 Sengokul-chome, Bunkyo-ku, Tokyo, Japan; said Matuo assignor to said Ohki NoDrawing. Filed Sept. 20, 1972, Ser. No. 290,596 Int. Cl. C07d 27/50 US.Cl. 260-247.2 A 12 Claims ABSTRACT OF THE DISCLOSURE A series ofS-endo-benzoyloxy-N-[amino(lower)alkyl]bicyclo[2.2.1]heptane2,3-di-end0-carboxylic acid imides have been foundto possess unique prophylatic and therapeutical activity ananti-arrhythmia agents. An example of such a compound possessingexcellent activity is -erzdo-benzoyloXy-N-(3dimethylaminopropyl)bi-cyclo- [2.2.1]heptane-Z,3-di-endo carboxylic acidimide hydrochloride.

A. British Pat. No. 1,042,840 describes compounds having the formula inwhich each of R and R" represent hydrogen, or together an alkylene grouphaving 1 or 2 carbon atoms, and R represents an alkyl group having 6 to18, preferably 8 to 12 carbon atoms in a straight chain as havingparticularly advantageous properties as functional fluids.

B. US. Pat. No. 2,393,99 describes the compound having the formula i HQM as being an eifective insecticide.

C. US. Pat. No. 2,424,220 describes the compound having the formula asbeing an effective insecticide.

3,850,921 Patented Nov. 26, 1974 ice D. US. Pat. No. 2,462,835 describesthe compound having the formula in which R is alkyl, al kene, aryl,substituted aryl, alkynl, etc. as insecticides.

E. Culberson and Wilder, Jr., J. Org. Chem., 25, pp. 1358 62 (1960)report the preparation of compounds having the formula in which R is CHC H or hydrogen.

F. Rice, lReide and Grogan, J. Org. Chem, 19, pp. 884-893 (1954) reportthe preparation of compounds of the formula 0 ll II o 0 0 in which R isalkyl and their subsequent reduction with lithium aluminum hydride.

G. Worrall, J. Am. Chem. Soc, 82, pp. 5707-5711 (1960) reports thepreparation of compounds having the formula o=c-mi O=CNH Br B O and I OCONE Ho 0 NH H. German Auslegeschrift No. 1,179,205 reports thepreparation of compounds having the formula in which thebicyclo[2.2.2]octane ring system in saturated or unsaturated and/orsubstituted, R and R are alkyl or alkenyl groups of 1 to 5 carbon atoms,or when combined with the nitrogen a heterocyclic ring. R is a(lower)alkyl group, n is a number of 2 to 5 and X a halogen anion. Thequaternary compounds are described as having therapeutic properties inthe treatment of cardiovascular disease, specifically high bloodpressure.

3 SUMMARY OF THE INVENTION wherein R R or R is H, Cl, Br, F,(lower)alkyl, nitro, OH or (lower)alkoxy, n is an integer of 2 to 4inclusive and R or R is H, (lower)alkyl or when taken together with thenitrogen a radical of the formula in which R is (lower)alkyl or apharmaceutically acceptable acid addition salt thereof areanti-arrhythmic agents.

Cardiac arrhythmia, a phenomenon commonly associated with coronary heartdisease or myocardial infarction, is an affliction not uncommon inhumans, especially the elderly. The mechanism of cardiac arrhythmia issuspected to be caused by an abnormal focus in the ventricle of theheart which sends out (fires) nerve signals more rapidly than requiredfor the normal beating of the heart. Uncontrolled arrhythmia can lead tofibrillation which results in death.

It has been discovered that the series of compounds herein designatedS-endo-benzoyloxy-N-[amino-(lower) alkyl]bicyclo[2.2.1]heptane-2,3-di-end0-carb oxylic acid imides having the formula v 7 2 R1 0 2 i R Q14 o 0 CH -N 3 R I wherein R R or R is H, Cl, Br, F, (lower)all yl,nitro, OH or (lower)alkoxy, n is an integer of 2 t0 4 inclusive and R orR is H, (lower)alkyl or when taken together with the nitrogen a radicalof the formula -N o 4v in which R is (lower)all yl; or apharmaceutically acceptable acid addition salt thereof are usefultherapeutic or prophylactic agents in the suppression of the abnormalectopic beat.

Compound I can theoretically exist in several isomeric forms, namely;

. endo-aroyloxy:endo-substituted imide;

. exo-aroyloxy:exo-substituted imide (X); endo-aroyloxy:exo-substitutedimide; and exo-aroyloxy:endo-substituted imide.

cage formed by carbon atoms 2, 3, 5 and 6, then we have the endo-endoisomer. When the constituent bond at position 5 is on the same side asthe C bridge and the constituents bond 2 and 3 are on the opposite sideof the 0, bridge, then we have the eX0(5p0sition)-endo- (2,3-position)isomer. When the constituent bond at position 5 is on the opposite sideof the C bridge and the constituents bonds 2 and 3 on the same side asthe C bridge. Illustrative of the exo-exo isomer is the compound havingthe formula CH o 3 Q" Illustrative of endo-endo is the compound offormula I.

The only isomers claimed in this invention are the endoendo isomers asrepresented by compound I and the dextroand levorotatory isomersthereof. The endo-endo isomers are inherently exclusively produced bythe synthesis described herein.

Some exo-endo isomers have been prepared by another synthetic route andhave been found to be inactive in regulating cardiac arrhythmia, e.g.,5-ex0-benzoyloxy-N-(3- dimethylaminopropyl) bicyclo[2.2.1]heptane 2,3diendo-carboxylic acid imide hydrochloride.

The optical isomers can be separated and isolated by fractionalcrystallization of the diastereoisomeric salts formed, for instance,with or ()-tartaric acid or D-()-camphor sulfonic acid (seeexperimental).

For the purpose of this disclosure, the term (lower) alkyl is defined asan alkyl radical containing 1 to 6 carbon atoms. The term (lower)alkoxyis an alkoxy radical containing 1 to 6 carbon atoms. The termpharmaceutically acceptable acid addition salt is defined to include allthose inorganic and organic acid salts of the compounds of the instantinvention, which salts are commonly used to produce nontoxic salts ofmedicinal agents containing amine functions. Illustrative examples wouldbe those salts formed by mixing the compounds of for mula I withhydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic,maleic, ascorbic, citric or tar.- taric, pamoic, lauric, stearic,palmitic, oleic, myristic, laurylsulfonic, naphthalenesulfonic, linoleicor linolenic acid, and the like.

A preferred embodiment of the present invention is the compound havingthe formula in which R is (lower)alkyl; or a pharmaceutically acceptableacid addition salt thereof,

Another preferred embodiment of the present invention is the compoundhaving the formula wherein R R or R is H, Cl, Br, F, (lower)alkyl,nitro, OH or (lower)alkoxy, n is an integer of 2 to 4 inclusive and Rand R is H, (lower)alkyl or when taken together with the nitrogen aradical of the formula -N o -N N-R6 in which R is (lower)alkyl; or apharmaceutically acceptable acid addition salt thereof.

Another preferred embodiment is the compound of formula Ia wherein R Ror R is H, F, Cl, nitro or (lowcr)alkoxy R and R are H, (lower)alky1 orwhen taken together with the nitrogen a radical of the formula Anotherpreferred embodiment is the compound of formula Ia wherein R R and R are(lower)alkoxy, R and R are (lower)alkyl or when taken together with thenitrogen a radical of the formula Another preferred embodiment is thecompound of formula Ia wherein R and R are hydrogen, R is N hydrogen orchloro, R and R are (lower)alkyl or when taken together with thenitrogen a radical of the formula or N 0 A more preferred embodiment isthe compound of formula Ia wherein R and R are hydrogen, R is chloro, nis an integer of 3 and R and R are methyl; or the hydrochloride saltthereof.

A most preferred embodiment of the present invention is the compound offormula Ia wherein R R and R are hydrogen, n is an integer of 3 and Rand R are methyl; or the hydrochloride salt thereof.

A more preferred embodiment is the compound of formula Ia wherein R Rand R are hydrogen, n is an integer of 2 and R and R are methyl; or thehydrochloride salt thereof.

A more preferred embodiment is the compound of formula Ia wherein R andR are hydrogen, R is nitro, n is an integer of 3 and R and R takentogether with the nitrogen is a radical of the formula or thehydrochloride salt thereof.

A more preferred embodiment is the compound of formula Ia wherein R Rand R are methoxy, n is an integer of 3 and R and R are methyl; or thehydrochloride salt thereof.

A more preferred embodiment is the compound of formula Ia wherein R Rand R are methoxy, n is an integer of 2 and R and R are methyl; or thehydrochloride salt thereof.

A more preferred embodiment is the compound of formula Ia wherein R andR are hydrogen, R is chloro,

6 n is an integer of 3 and R and R taken together with the nitrogen is aradical of the formula of the hydrochloride salt thereof.

A more preferred embodiment is the compound of formula Ia wherein R andR are hydrogen, R is nitro, n is an integer of 3 and R and R when takentogether with the nitrogen is a radical of the formula N O of thehydrochloride salt thereof.

A more preferred embodiment; is the compound of formula Ia wherein R andR are hydrogen, R is chloro, hydrogen or nitro, n is an integer of 3 andR and R are each (lower)alkyl; or the hydrochloride salt thereof.

A more preferred embodiment is the compound of formula Ia wherein R andR are hydrogen, R is nitro, n is an integer of 3 and R and R are methyl;or the hydrochloride salt thereof.

A most preferred embodiment is the levorotatory isomers of the compoundof formula la.

Another most preferred embodiment is the dextrorotatory isomers of thecompound Ia.

The most preferred embodiment of the present invention is thedextrorotatory isomer of the compound Ia wherein R R and R are hydrogen,n is 3 and R and R are methyl; or the hydrochloride salt thereof.

Another most preferred embodiment of the present invention is thelevorotatory isomer of the compound Ia wherein R R and R are hydrogen, nis 3 and R and R are methyl; or the hydrochloride salt thereof.

The objectives of the present invention have been achieved by theprocess of preparing the compounds having the formula wherein R R or Ris H, Cl, Br, F, (lower) alkyl, nitro, 'OH or (lower)alkoxy, n is aninteger of 2 to 4 inclusive and R or R is H, (lower)alkyl or when takentogether with the nitrogen a radical of the formula B. Treating 1 moleof compound II with at least one mole of acetyl chloride or phosphoroustrichloride at reflux temperature for at least 15 minutes and removingthe excess acetyl chloride or phosphorous trichloride in vacuo toproduce an oily residue IIa;

C. Treating residue IIa with at least one mole of an amine having theformula s NH2(CH1) N in which n is an integer of 2 to 4 inclusive, R orR are H, (lower)alkyl or when both are taken together with the nitrogena radical of the formula in which R' is (lower)alkyl; in an organicsolvent, preferably selected from the group comprising benzene, toluene,xylene, and the like at about reflux temperatures for at least 30minutes and removing the solvent in vacuo to produce an oily residueIIb;

D. treating residue Ilb with at least one mole of potassium hydroxide ina mixture of a (lower)alkanol and water with the aid of heat, butpreferably at reflux temperature for at least one hour to produce thecompound having the formula III in which n, R and R are as above; and

E. treating one mole of compound III with at least one mole of a benzoylhalide, or its chemical equivalent, having the formula 0 if L X 2 inwhich R R and R are as defined above and X is chloro, bromo or iodo, butpreferably chloro, in an organic solvent, preferably selected from thegroup comprising benzene, toluene, xylene, pyridine, but preferablypyridine, in a temperature range of 0 C. to 60 C., but preferably atabout room temperature to yield compound I.

PHARMACOLOGY LDso with 95% Comconfidence Species pound limits, ing/kg.

Mouse Ib 26 (23-20. 4) V 43.5 107-26. 5)

Rat lb 25 (23. 6-26. 5) V 39 (35. 942. 3)

The compounds were tested in dogs for their reversion activity inouabain-induced arrhythmia:

Anesthetized dogs were used for the production of ouabain-inducedventricular arrhythmias. The arrhythmia consisted of a nodal orventricular tachycardia. The procedure used to establish the arrhythmiaas well as the criteria employed to determine anti-arrhythmic activitygenerally was that employed by Lucchesi et al. Intravenous infusion of1b, V and VI was done at a rate of 0.2 mg./kg./min. and compared tolidocaine and quinidine. The average reverting doses are shown below.

Reverting Dose,

The compounds were also tested for their reversion of ventriculararrhythmia due to coronary artery ligation in conscious dogs:

Multifocal ventricular ectopic rhythms were produced in dogs accordingto the coronary artery ligation method of Harris Approximately 24 hoursafter induction of the ventricular arrhythmia the test drugs wereinfused at a rate of 0.2 mg./kg./min. The approximate average dosesnecessary to produce a 50% decrease in the number of ventricular ectopicbeats, and toproduce reversion of the ventricular arrhythmia are shownbelow. In contrast to 1b and VI, no reversion was observed with anintravenous infusion of lidocaine or quinidine in doses of up torng./kg.

Dose 3;) producing 50% reduction in ectopic Rvert- Compound beats ingdose Ib 2. 4. 10 v 3. 3 11 3. 0 7 Lidoeaine 20 20 Quinidine 10. 1 20 Allthe compounds within the scope of the present invention-possessanti-arrhythmic activity.

' The compounds of the present invention are useful in the treatment ofcardiac arrhythmia in mammals, including man, as prophylactic ortherapeutic agents in doses in the range of 0.25 mg. to 3.0 mg./kg. upto 3 or 4 times a day.

EXPERIMENTAL EXAMPLE 1 Preparation ofBicyclo[2.2.1]heptane-endo-Z,S-dicarboxylicacid-S-endo-hydroxy-y-lactone (II) Lucchesi. B. L. and I Hardman: Theinfluence ol dichloroiso' proterenol (DCI) and related compounds uponouabain and acetylstrophanthidin induced cardiac arrhythmias. J Pharmacol. Exp. Thcrap., 1321372, 1061.

2 Harris, A. S. Delayed development of ventricular ectopic rhythmsfollowing experimental coronary occlusion. Circulation 1:1318, 1950.

EXAMPLE 2 General Method of Preparation of S-endO-HydroXy-N-[amino(lower)alkyl]bicyclo[2.2.1]heptane 2,3 diendo-carboxylic AcidImides (III) R III A mixture of 0.1 mole of lactone (II) from example 1and 50 ml. of acetyl chloride was refluxed on a water bath for twohours. The excess acetyl chloride was removed in vacuo and an oilyresidue (IIa) remained that was washed with n-hexane (or petroleumether). The oily residue was dissolved in 50 ml. of anhydrous benzene.To this solution was added a solution of 0.12 moles of the ap propriateamine, e.g., N,N-dimethylaminopropylamine, and 100 ml. of anhydrousbenzene with stirring. The mix ture was then refluxed for about fivehours and concentrated in vacuo. The resultant brown syrupy substance(IIb) was refluxed for five hours in 300 ml. of 0.12 mole of potassiumhydroxide and 50% water-ethanol. The solvents were removed in vacuo,saturated potassium carbonate solution added and the resultant solutionextracted repeatedly using chloroform or 1:1 ethyl acetate-benzene. Thecollective organic extracts were washed with saturated sodium chloridesolution and dried over anhydrous sodium sulfate. After filtration, thesolution was concentrated in vacuo and the product was recovered bycrystallization, chromatography and/ or vacuum distillation wherein informula III, n is an integer of 2 to 4 inclusive, R or R is H,(lower)alkyl or when taken together with the nitrogen a radical of theformula in which R is (lower) alkyl.

EXAMPLE 3 -N N-R6 The S-endo-Hydroxy-N- [amino (lower)alkyl] bicyclo-[2.2.1]heptane-2,3-di-endo-carboxylic acid imide (III) (0.01 mole)obtained in example 2 was added to 50 ml. of a 100:1 pyridinepiperidinesolution of 0.012 mole of an appropriate benzoyl halide, e.g., benzoylchloride, with stirring. The resultant mixture was allowed to standovernight in a refrigerator or warmed in a wateror oil-bath. The mixturewas poured into ice-water and saturated with sodium carbonate and thenextracted with chloroform or 1:1 benzeneethyl acetate. The combinedorganic extracts were washed with saturated sodium chloride solution anddried over anhydrous sodium sulfate. The solution was collectedfiltration and concentrated in vacuo to yield the desired title product(1).

10 EXAMPLE 4 Alternate Method of Preparation of S-endo-Hydroxy-N-[amino(lower)alkyl]bicyclo[2.2.1heptane] 2,3 diendo-carboxylic AcidImides (III) A mixture of 0.1 mole of lactone (Ila) from example aboveand 30 ml. of PCl was refluxxed in a water bath for two hours. Theexcess PCl was removed in vacuo and washed with n-bexane. The oilyresidue was dissolved in. 50 ml. of chlosoform or methylene chloride anda solution of 0.12 mole of an appropriate amine, e.g.,N,N-dimethylaminopropylamine, dissolved in ml. of anhydrous chloroformor methylene chloride was added with stirring and cooling. Stirring wascontinued for two hours, following which the mixture was warmed to roomtemperature following which the mixture was refluxed for about 15minutes. The solution was washed with saturated potassium carbonatesolution after cooling, separated, and the organic phase washed withsaturated sodium chloride solution. The organic solution was dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Thematerial subsequently collected was the title product of formula IIIwherein n is an integer of 2 to 4 inclusive, R or R is H, (lower)alkylor when taken together with the nitrogen a radical of the formula -u o-N N-R6 I or i in which R is (lower)alkyl.

EXAMPLE 5 Preparation of5-end0-Hydroxy-N-(3-dimethylaminopropyl)-bicyclo[2.2.1]-heptane-2,3 diendo carboxylic Acid Imide (IIIa) H 0 -CH2-CH2-CH2N\CH IIIa. 3

Substitution in the procedure of example 2 or 4 of an equimolar quantityof N,N-dimethylarninopropylamine for the appropriate amine used thereinproduced the title product as colorless plates when crystallized fromethanol-n-hexane; m.p. 148 C. (1% H O) or 154 C. /s H O). Yield: 26-37%.

Anal.Calcd. for C14H22O3N2'1% H O: C, 56.42; H, 8.79; N, 9.40. Found: C,56.70; H, 8.76; N, 9.11.

AnaL-Calcd. for C H O N /3 H O: C, 61.76; H, 8.45; N, 10.29. Found: C,61.93; H, 8.76; N, 10.40.

EXAMPLE 6 Preparation of S-emlo-BenzoyloxyN-(3-dimethylaminopropyl)-bicyclo[2.2.1]heptane 2,3 di-endo-carboxylicAcid Imide (lb) A. Substitution in the procedure of example 3 of anequlmolar quantity of benzyol chloride for the appropriate benzoylhalide used therein and for the dicarboxylic acid imide III an equimolarquantity of IIIa obtained in example produced the title product whichwas collected as the hydrochloride salt.

B. The free base was dissolved in near boiling ethanol (700 ml.) and 90ml. of ethanol saturated with hydrogen chloride gas was added. Thesolution was cooled with ice to produce colorless plates of thehydrochloride salt of formula Ib; m.p. 239 C. with decomposition uponrecrystallization from methanolacetone. Yield90%.

Anal.-Calcd. for C21H270'4N2C1% H: C, H, 6.83; N, 6.95. Found: C, 60.63;H, 6.88; N, 7,33.

EXAMPLE 7 Preparation of 5-end0-3,4,5 Trimethoxybenzoyloxy-N- (3dimethylaminopropyl) bicyclo[2.2.l]heptane- 2,3-di-endo-carboxylic AcidImide Hydrochloride (1c) Substitution in the procedure of example 3 forthe appropriate benzoyl halide used therein of an equimolar quantity of3,4,5-trimethoxybenzoyl chloride and for the dicarboxylic acid imide IIIan equimolar quantity of IIIa produced the title compound which wascollected as the hydrochloride salt (using a method equivalent to thatemployed in example 6B). The hydrochloride was collected as colorlessplates upon recrystallization from water-ethanol; m.p. 250.2 C.; yield:22%.

ArzaL-Calcd. for C24H3107N2'HC1'H2OI C, 56.96; H, 6.77; N, 5.54. Found:C, 56.64; H, 6.76; N, 5.59.

EXAMPLE 8 Preparation of S-endo 4 NitrobenzoyloxyN-(3-dimethylaminopropyl)-bicyclo[2.2.l]heptane 2,3 diendo-carboxylicAcid Imide Hydrochloride (Id) Substitution in the procedure of example 3for the appropriate benzoyl halide used therein of an equimolar quantityof 4-nitrobenzoyl chloride and for the dicarboxylic acid imide III anequimolar quantity of IIIa produced the title compound which wascollected as the hydrochloride salt (using a method comparable to thatemployed in example 6B). The hydrochloride salt was collected as paleyellow plates upon recrystallization from water-ethanol; m.p. 197 C.Yield: 30%.

AnaL-Calcd. for C H O N -HCl'2I-I O2 C, H, 6.20; N, 8.61. Found: C,51.35; H, 6.35; N, 8.58.

EXAMPLE 9 Preparation of 5-end0 4Chlorobenzoyloxy-N-(3-dimethylaminopropyl)bicyclo[2.2.l]heptane 2,3diendo-carboxylic Acid Imide Hydrochloride (Ie) Substitution in theprocedure of example 3 for the appropriate benzoyl halide used thereinof an equimolar quantity of 4-chlorobenzoyl chloride and for thedicarboxylic acid imide III an equimolar quantity of Illa produced thetitle compound which was collected as the hydrochloride (using a methodcomparable to that employed in example 6B). The hydrochloride wascollected as colorless plates upon recrystallization from waterethanol;m.p. 208 C. 1

Anal.Calcd. for C H O N Cl-1 /zH O: C, 54.01; H, 6.26; N, 6.00. Found:C, 53.84; H, 5.91; N, 6.14.

EXAMPLE 10 Preparation of5-ena'0-Hydroxy-N-(2-dimethylaminoethyl)bicyclo[2.2.l]heptane-2,3-di-end0carboxylic Acid Imide (IIIb) Substitution in the procedure of example 4for the appropriate amine used therein of an equimolar quantity ofN,N-dimethylethylamine produced the title product 12 which was collectedas the hydrochloride using a method comparable to that employed inexample 6B. The free base was collected as colorless plates uponrecrystallization from ethanol-n-hexane; m.p. 141.5 C. Yield: 50%.AnaZ.- Calcd. for C H O N /3H O: C, 60.46; H, 8.13; N, 10.85. Found: C,60.71; H, 8.04; N, 10.95.

EXAMPLE 11 Preparation of S-endo-Hydroxy N(Z-diethylarninoethyl)bicyclo[2.2.l]heptane-2,3-di-elzd0 carboxylic AcidImide Phenolphthalinate (IIIc) Substitution in the procedure of example2 for the appropriate amine used therein of an equivalent amount ofN,N-diethylaminoethylamine produced the title product as yellow oil,b.p. 213220 C./5 mm. Hg. Yield: 37%. The product was furthercharacterized as the phenolphthalinate salt, m.p. 137.8138.8 C.

Anal.Calcd. for C H O N '1 /2H O: C, 67.04; H, 6.91; N, 4.48. Found: C,67.38; H, 7.41; N, 4.23.

EXAMPLE 12 Preparation of 5-end0-3,4,5-trimethoxybenzoyloxy-N-(2-diethylaminoethyDbicyclo[2.2.l]heptane-2,3-di endocarboxylic Acid ImideHydrochloride (If) EXAMPLE 13 Preparation of 5-end0-Hydroxy-N-(3diethylaminopropyl)bicyclo[2.2.1]heptane-2,3-di-end0-carboxylic AcidImide Phenolphthalinate (IIIf) Substitution in the procedure of example2 for the appropriate amine used therein of an equivalent amount ofN,N-diethylaminopropylamine produced the title product as a yellow oil,b.p. 228230 C./6 mm. Hg. Yield: 34%. The product was furthercharacterized as the phenolphthalinate salt, m.p. 158 C.

Anal.Calcd. for C3 H42O7N2'1 AlH2O: C, H, 7.02; N, 4.36. Found: C,67.77; H, 6.79; N, 4.36.

EXAMPLE 14 Preparation of S-endo-Hydroxy-N-(3-piperidinopropyl)bicyclo[2.2.1]heptane 2,3 di-endo-carboxylic Acid Imide (IIIe) a aa lIIIe Substitution in the procedure of example 4 for the appropriateamine used therein of an equivalent amount of 3-piperidinopropylamineproduced the title product as colorless plates upon recrystallizationfrom isopropanoln-hexane, m.p. 121.5" C. Yield: 50%.

Allfll.-C211Cd. fol C HggOgNg'Ml-H OI C, H, 8.53; N, 9.01. Found: C,66.05; H, 9.03; N, 9.06.

OEPO

'13 EXAMPLE 15 Preparation of 5-end0-Hydroxy-N-(2-morpholinoethyl)bicyclo[2.2.1]heptane 2,3 di-endo-carboxylic Acid Imide Hydrochloride(Inf) H o ir-cn -ca -N 0 III)? Substitution in the procedure of example2 or 4 for the appropriate amine used therein of an equivalent amount ofmorpholinoethylamine produced the title compound which was collected asthe hydrochloride (using a method comparable to that employed in example6B). The hydrochloride was collected as colorless plates uponrecrystallization from water-ethanol, m.p. 280282 C. Yield: 30-34%.

AnaL-Calcd. for C H O N -HCh C, 54.43; H, 7.00; N, 8.46. Found: C,54.26; H, 7.56; N, 8.50.

EXAMPLE 16 Preparation of S-endo-Hydroxy-N-(3-morpholin0propyl)-bicyclo-[2.2.1]heptane 2,3 di-endo-carboxylic Acid Imide (IIIg)Substitution in the procedure of example 2 for the appropriate amineused therein of an equivalent amount of morpholinopropylamine producedthe title product as a yellow oil, b.p. 260270 C./4 mm. Hg; yield 50%.The product was further characterized as the methiodide salt; mp. 233 C.

. AnaI.Calcd for C H O N -CH I: N, 6.20. Found: N, 6.28.

EXAMPLE 17 Preparation of -cnd0-4-Nitrobenzoyloxy-N-(3-morpholinopropyl)bicyclo [2.2.1]heptane-2,3-di-end0-carboxylic acid Imide (lg)Substitution in the procedure of example 3 for the appropriate benzoylhalide used therein of an equivalent amount of 4-nitrobenzoyl chlorideand for the dicarboxylic acid imide III used therein an equimolarquantity of 111g produced the title product as colorless plates uponcrystallization from acetone-n-hexane, m.p. 182.5

AnaL-Calcd for c n o rnz c, 60.39; H, 5.91; N, 9.19. Found: c, 60.58; H,6.32; N, 9.28.

EXAMPLE 18 Preparation of5-end0-4-Chlorobenzoyloxy-N-(3-morpholinopropyl) bicyclo[2.2.1]heptane2,3 di-endo-carboxylic acid Imide Hydrochloride (Ih) EXAMPLE 19 GeneralProcedure for the Preparation of the racemic 5 endo benzyloxy N[amino(lower)alkyl] bicyclo- [2.2.1]heptane-2,3-di-endo-carboxylic AcidImides into its and Entantiomers 1. Treatment of the racemic base with(+)--camphor-sulfonic acid in ethanol-water gave the diastereoisomericsalt of the (-)-isomer. Decomposition of this salt with aqueous sodiumcarbonate afforded the ()-enantiomer which was converted to thehydrochloride with ethanolic hydrogen chloride.

2. The mother liquor from the first step was concentrated to leave amixture of diastereoisomeric salts. Neutralization of this mixture wasaqueous sodium carbonate gave a mixture of the and ()-isorners, whichwas greatly enriched in the (+)-enantiomer. In one small scaleexperiment it was possible to obtain substantially pure (+)-isomer byrecrystallization from cyclohexane. In larger scale experiments it wasmore expedient to purify the mixture through diastereoisomer formationwith (-)-tartaric acid to give the salt of ()-tartaric acid with the(+)-enantiomer, which is subsequently decomposed to produce the(+)-enantiomer.

EXAMPLE 20 Resolution of (1) 5 end0-Benzoy10xy-N-(3-Dimethylaminopropyl) Bicyclo[2.2.1]Heptane 2,3 di-endo- CarboxylicAcid Imide Hydrochloride (lb) I. Preparation of the (-)-enantiomer A.(m) S-endo-Benzoyloxy-N-(3-dimethylaminopr0- pyl) bicyclo[2.2.1]heptane2,3-di-end0-carboxylic Acid Imide (lb): A stirred mixture of thehydrochloride salt of lb (10 g.) in water ml.) and ether (200 ml.) wasneutralized by the addition of sodium carbonate. The aqueous layer wasreextracted with ether (2X 200 ml.). The combined ethereal extracts werewashed with water, followed by water saturated with sodium chloride (3X)and dried (sodium sulfate). Removal of the ether left colorless crystalsof the racemic base lb (9.3 g.), m.p. 106-1075.

B. (+)-10-Camphorsulfonic Acid Salt of ()-5-en.d0- benzoyloxy N(3-dimethylaminopropyl)bicyclo[2.2.1]- heptane-Z,3-di-cndo-carboxylicAcid Imide: A hot solution of (+)-1()-camphorsulfonic acid (276.5 g.,1.19 mole) in ethanol (1.1 l.) was added to a hot solution of theracemic base Ib (441.1 g., 1.119 mole) in ethanol (3.5 1.) containingWater ml.). The solution was heated to near boiling and then rapidlycooled to 20. The colorless crystaline material which formed during 3hours standing at 20 was collected and washed with cold ethanol (600ml.) to give 325.3 g. of the title product, m.p. 221226. The salt wasrecrystallized from acetonitrile to give colorless needles (282.6 g.),m.p. 230- 233. The ethanolic mother liquor was retained for isolation ofthe (+)-isomer.

C. )-5-end0-Benzoyloxy N(3-dimethylaminopropyl))bicyclo[2.2.1]heptane-2,3 di-endo-carboxylicAcid Imide: The camphorsulfonic acid salt from step B (282.6 g.) waspartitioned between a stirred mixture of ethyl acetate (3.5 l.) andwater (3 1.) containing sodium carbonate (150 g.). The aqueous layer wasre-extracted with ethyl acetate (600 ml.). The combined ethyl acetateextracts were Washed with water saturated with sodium chloride (3x), anddried (sodium sulfate). Removal of the ethyl acetate left the titleproduct as colorles crystals (173.3 g.): mp. 131.5132.5; 78.53 (c. 4.26,ethanol).

D. (-)-5-end0-Benzoyloxy N(3-dimethylamit1opropyl)bicyclo[2.2.1]heptane-Z,S-di-endo-carboxylicAcid Imide Hydrochloride (V): To a near boiling solution of the()-isomer (173.3 g., 0.468 mole) from step C in 95% ethanol (3.5 l.) wasadded 475 ml. of 95% ethanol, 0.988 molar in hydrogen chloride (0.468mole of HCl). The solution was cooled in ice. The colorless crystalswere collected, Washed with cold 95 ethanol (600 ml.) and dried to givethe title product (182.6 g.): m.p. 207-- 209"; [011 85.56 (c. 1.5,water). The m.p. and rotation were not significantly changed uponfurther recrystallization from 95% ethanol.

H. Preparation of the (+)-enantiorner A. ()-Tartaric Acid Salt of(+)5-end0-benzoyloxy- N (3dimethylaminopropyl)bicyclo[2.2.1]heptane-2,3-

di-endo-carboxylic Acid Imide: The ethanolic mother liquor from step IBabove was stored at for 90 hours to give additional crystalline material(237.2 g.), m.p. 183-186. The filtrate was concentrated to give anothercrop of colorless crystals (119.9 g.), m.p. 168-177. Both crops werecombined and partitioned between ethyl acetate and aqueous sodiumcarbonate as described in IC. above to give a mixture of and ()-isomers(221.4 g.), m.p. 125-429, greatly enriched in the (+)-enantiomer.

-)-Tartaric acid (89.6 g., 0.596 mole) was added to a hot stirredsolution of the )-enriched mixture (221.4 g., 0.596 mole) in ethanol(3.6 1.) containing water (40 ml.). The stirred mixture was heated tonear boiling and then cooled to 25 during 4 hours. The colorlesscrystalline material was collected, washed with cold 95% ethanol (500ml.) and dried to give the tartrate salt of the enantiomer (291.6 g.),m.p. 157-161 (dec.). Recrystal lization from acetonitrile gave 247.2 g.of the purified tartrate salt, m.p. 162-164 (dec.).

B. (+)-5-end0-Benzoyloxy N (3-dimethylaminopropyl)bicyclo[2.2.1]heptane2,3-di-end0-carboxylic Acid Imide: The tartrate salt from step A (247.2g.) was decomposed With aqueous sodium carbonate and the liberated(+)-enantiomer extracted into ethyl acetate as described in IC. Removalof the ethyl acetate left the (+)-is0mer (171.6 g.), as colorlesscrystals: m.p. 131- 133.5; [M +77.74 (c. 1.89, ethanol).

C. (+)-5-end0-Benzoyloxy N (3-dimethylarninopropyl)bicyclo[2.2.1]heptane2,3 di-endo-carboxylic Acid Imide Hydrochloride (VI): The (+)-enantiomer(171.6 g.) from step B was treated with an equivalent of ethanolichydrogen chloride as described for the )-enantiomer in ID. to givecolorless crystals of the enantiomer HCI, (188.2 g.): m.p. 207-209";[111 +85.88 (c. 1.36, water).

EXAMPLE 21 Preparation ofS-endo-Benzoyloxy-N-(Z-dimethylaminoethyl)bicyclo[2.2.1]heptane 2,3 diendo-carboxylic Acid Imide (Ij) Substitution in the procedure of example3 for the appropriate benzoyl halide used therein of an equimolarquantity of benzoyl chloride and for the dicarboxylic acid imide anequimolar quantity of IIIb obtained in Example 13, produces the titlecompound.

EXAMPLE 22 Preparation of 5-end0 4Nitrobenzoyloxy-N-(3-piperidinopropyl)bicyclo[2.2.1]heptane 2,3di-endo-carboxylic Acid Imide (Ik) Substitution in the procedure ofexample 3 for the appropriate benzoyl halide used therein of anequimolar quantity of 4-nitrobenzoyl chloride and for the dicarboxylicacid imide III used therein of IIIe produced the title compound.

EXAMPLE 23 EXAMPLE 24 Preparation of5-end0-3,4,S-Trimethoxybenzoyl-N-(2-dimethylaminoethyl)bicyclo[2.2.1]heptane2,3diend0- carboxylic Acid Imide (Im) Substitution in the procedure ofexample 3 for the appropriate benzoyl halide used therein of anequimolar quantity of 3,4,5-trimethoxybenzoyl chloride and for the 16dicarboxylic acid imide III used therein an equimolar quantity of IIIbproduced the title compound.

Anal.Calcd. for C H O N HCl 1/ 3 H O: C, 56.44; H, 6.54; N, 5.71. Found:C, 56.63; H, 7.08; N, 5.91.

EXAMPLE 25 Preparation of 5 endo-Benzoyloxy-N-(3methylarninopropyl)bicyclo[2.2.1]heptane-2,3-di-endo carboxylic AcidImide Hydrochloride (Ij).

A. 5-endo-Benzoyloxy-N-[3 (2,2,2 trichloroethoxycarbonyl) 3methylaminopropyl]bicyclo[2.2.1]heptame-2,3-di-end0-carboxylic AcidImide: Under anhydrous conditions there was added 4.66 g. (22 mmoles) oftrichloroethyl chloroformate to a mixture of 3.7 g. (10 mmoles) ofcompound Ib and 2.0 g. (14.5 mmoles) potassium carbonate in 50 ml.benzene. The reaction mixture was refluxed for 18 hours. After cooling,ethyl acetate was added and the solution was filtered from theinsolubles. The filtrate was washed with water, 5% K CO water, 5% HCl,water and brine. After drying (Na SO and filtration the solvents wereevaporated. In this manner there was obtained a crude product which whenrecrystallized from ethyl acetate-Skelly B (essentially n-hexane)afforded 3.5 g. (65.7%) of pure title product; m.p. 104- 107 C.

Anal.-Calcd. for C H Cl N O t C, H, 4.74%; N, 5.27%. Found: C, 51.75%;H, 4.76%; N, 5.08%.

B. 5-end0-Benzoyloxy N (3-methylaminopropyl)bicyclo[2.2.1]heptane-2,3di-endo-carboxylic Acid Imide Hydrochloride: Zinc dust (11.0 grams) wasadded to a solution of 5.56 g. (10.5 mmoles) of the compound prepared inA above in 120 ml. of acetic acid. The resulting reaction mixture wasstirred at room temperature for four hours. The mixture was filtered andthe filtrate evaporated to dryness. The residue was made basic by theaddition of sodium bicarbonate and again was evaporated to dryness.Benzene (500 ml.) and Na SO was added to the residue. The mixture wasfiltered; the filtrate was evaporated and the residue was dissolved inmethanol. Some ether was added, and the hydrochloride salt was preparedwith anhydrous hydrogen chloride gas. The precipitated salt wascollected and after several recrystalliz'ations from methanol-ether,there was obtained a 72% yield of title compound (Ij), m.p. l96199 C.

Anal.Calcd. for C H N O -HCl-02 H O: C, 60.45%; H, 6.40%; N, 7.05%; KF,1.13%. Found: C, 60.62%; H, 6.44%; N, 7.04%; KF, 1.83%.

EXAMPLE 26 Preparation ofS-endo-Benzoyloxy-N-(3-aminopropyl)bicyclo[2.2.1]heptane-2,3 di endocarboxylic Acid Imide (Ik) 0 Gt. 0 a- Q- a- Z A. 5-endo-Hydroxy-N-(3cyanoethy1)bicyclo[2.2.l]- heptane-2,3-di-end0-carboxylic Acid Imide(XI): Substitution in the procedure of examples 2 or 4 for theappropriate amine used therein of an equimolar quantity of 2-cyanoethylamine produces the title compound.

B. S-endo-Benzoyloxy-N-(3-cyanoethyl)bicyclo[2.2.1]-heptane-2,3-di-endo-carboxylic Acid Imide (XI): Substitution in theprocedure of example 3 for the appropriate benzoyl halide used thereinof an equimolar quantity of benzoyl chloride produces the title compoundX.

C. S-endo-Benzoyloxy N (3 aminopropyl)bicyclo[2.2.1]-heptane2,3-di-end0-carboxylic Acid Imide (IIIk): One-tenth mole of compound XIprepared in B above is dissolved in 200 ml. of ethanol and hydrogenatedat 60 p.s.i. using Pd/ C and hydrogen till two-tenths mole of hydrogenis absorbed to produce compound Ik.

17 I claim: 1. A compound having the formula i 1 on CH N\R in which n isan integer of 2 to 4 inclusive and each of R and R are H or (lower)alkylor when taken together with the nitrogen a radical of the formula inwhich R is (lower)alkyl; or an acid addition salt thereof.

2. A compound of claim 1 wherein each of R and R' are H or (lower)alkylor when taken together with the nitrogen a radical of the formula N or NO.

3. A compound of claim 1 wherein each of R and R are (lower) alkyl orwhen taken together with the nitrogen a radical of the formula 18 6. Thecompound of claim 1 wherein n is an integer of 3, and R and R takentogether with the nitrogen is a radical of the formula or thehydrochloride salt thereof.

7. The compound of claim 1 wherein n is an integer of 3 and R and Rtaken together with the nitrogen is a radical of the formula or thehydrochloride salt thereof.

8. The compound of claim 1 wherein n is an integer of 3 and R and R areeach (lower) alkyl; or the hydrochloride salt thereof.

9. A compound of claim 1 wherein n is an integer of 2 to 4 inclusive andR is H, R is H or (lower)a1ky1; or an acid addition salt thereof.

16. A compound of claim 9 Whereni R is H, methyl, ethyl or propyl.

11. The compound of claim 9 wherein R is methyl.

12. The compound of claim 9 wherein R is H.

References Cited UNITED STATES PATENTS 3,084,167 4/1963 Rice 260319FOREIGN PATENTS 1,570,452 6/1969 France 26O--247.2

OTHER REFERENCES Hulsgen, R et al.: Angew. Chem. Int. Ed Gngl., 1969,8(8), 604.

LORRAINE A. WEINBERGER, Primary Examiner P. J. KILLOS, AssistantExaminer US. Cl. X.R. 260268 TR, 293.61, 326 C, 343.3; 424-248, 267, 274

1. A COMPOUND HAVING THE FORMULA